Michael A. Gelman 1997-2005
1st Year Resident, Internal Medicine
University of Washington Affiliated Hospitals - Seattle, WA
Harvard University 1997
Chemistry PhD 2003
Samuel Gellman
Synthesis and biological applications of cationic beta-peptides and styrenic polymers
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Beta-peptides, oligomers of beta-amino acids, can adopt regular secondary structures, especially when conformationally constrained residues are used to enforce torsional angles. However, conformational preorganization is not always required for biological activity. For example, translocation of peptides across cell membranes may depend only on the display of multiple guanidinium groups. Blocking of the interaction between the HIV-1 Tat protein and HIV-1 TAR RNA, a critical step in the life cycle of the AIDS virus, also appears to depend only on the presentation of arginine side chains in a cationic context. The antimicrobial activity of peptides also may not depend on the adoption of an amphiphilic helical conformation. The all-beta-substituted beta-amino-acid homologue of the HIV-1 Tat 47;57 sequence (YGRKKRRQRRR) was synthesized, along with several analogues, and found to be unstructured in aqueous solution. This beta-peptide, tagged with fluorescein, was internalized in a fixed-cell assay. Truncation of the three C-terminal arginines abolished uptake, as it does for the parent alpha-peptide. This beta-peptide sequence also showed binding (Kd = 29 nM) to HIV-1 TAR RNA. Replacement of all arginine side chains by lysine side chains gave stronger but less specific binding. Copolymers of 4-(dimethylamino)methylstyrene with styrene, 4-isopropyl styrene, or 4-octylstyrene were synthesized by AIBN-initiated radical polymerization and assayed for antibacterial and hemolytic activity. These statistical copolymers are stereochemically random and should not be preorganized to form regular structure. Up to 20;30 mol% hydrophobic monomer, the polymers had inhibitory activity against Escherichia coli and Bacillus subtilis, as well as antibiotic-resistant clinical strains of Staphylococcus aureus and Enterococcus faecium, comparable to that of an activity-enhanced analogue of the antimicrobial peptide magainin. These polymers also show potent hemolytic activity. In sum, three systems have been explored in which biological activity is independent of structural preorganization. |
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| Thesis Publications |
- Gelman MA, Weisblum B, Lynn DM, Gellman SH. Biocidal activity of polystyrenes that are cationic by virtue of protonation. Org Lett 6:557-560, 2004.
- Gelman MA, Richter S, Cao H, Umezawa N, Gellman SH, Rana TM. Selective binding of TAR RNA by a Tat-derived beta-peptide. Org Lett 5:3563-3565, 2003.
- Umezawa N, Gelman MA, Haigis MC, Raines RT, Gellman SH. Translocation of a beta-peptide across cell membranes. J Am Chem Soc 124:368-369, 2002.
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